Abstract 4368979: Inhibition of Cardiac GLUT1 Suppresses KLF5 Activation and Ameliorates Diabetic Cardiomyopathy

Abstract

Introduction: Cardiomyocytes (CM) primarily rely on fatty acid oxidation (FA) for ATP production. Paradoxically, despite increased FA utilization in diabetes, humans and mice develop diabetic cardiomyopathy (DbCM). We previously identified KLF5 as a key mediator of DbCM via induction of lipotoxicity. Our new findings suggest that GLUT1 causes DbCM by combinedly igniting glucotoxicity and lipotoxicity. Methods and Results: Type 1 (T1D) and Type 2 (T2D) diabetes were induced in wild type mice (streptozotocin and high-fat diet, respectively). In accordance with our prior findings, cardiac KLF5 expression was increased at the late stage of T1D and T2D. Metabolomic analysis in late-stage T1D showed higher glucose that was associated with elevated GLUT1 expression. A new mouse line with CM-specific ablation of GLUT1 that we generated was protected from DbCM in both T1D and T2D. Accordingly, both preventive and therapeutic treatments with a GLUT1 small molecule inhibitor (STF31) reversed DbCM in mice with either T1D or T2D. The cardioprotective effect of STF31 in both T1D or T2D was associated with reduced glucose uptake (PET/CT), lower cardiac KLF5 expression and less oxidative stress (DHE staining). Metabolomic analysis showed increased antioxidant metabolites (tyrosine, serine), while lipidomic analysis revealed that GLUT1 inhibition lowered cardiac ceramide species in T2D and restored phospholipids (BMP, LPI, PI) in T1D hearts following GLUT1 inhibition. Western blotting analysis showed that cardiac O-GlcNAcylation, a known global post-translational modification of proteins in diabetes, was reduced by GLUT1 inhibition. To see if GLUT1 diverts glucose into non-ATP producing pathways, we measured key enzymes. Aldose reductase and O-GlcNAc transferase were elevated in diabetic hearts but normalized by GLUT1 inhibition. Additionally, GLUT1 inhibition partially reversed the diabetes-induced upregulation of pyruvate and FA transport and utilization-related genes ( Pdk4, Cpt1, Cd36 ), indicating restoration of cardiac metabolic homeostasis. Notably, GLUT1 inhibition prevented cardiac KLF5 upregulation. Accordingly, high glucose treatment of AC16 cells increased KLF5 and ceramide biosynthesis enzyme expression, suggesting that GLUT1 drives both glucotoxicity and lipotoxicity. Conclusion: In diabetes, glucose uptake via GLUT1 activates KLF5, drives gluco-lipotoxicity, and contributes to DbCM progression, making GLUT1 a promising therapeutic target.